Defective insulin and acetylcholine induction of endothelial cell-nitric oxide synthase through insulin receptor substrate/Akt signaling pathway in aorta of obese rats

Henrique G. Zecchin, Fernanda B.M. Priviero, Claudio T. Souza, Karina G. Zecchin, Patrícia O. Prada, José B.C. Carvalheira, Licio A. Velloso, Edson Antunes, Mario J.A. Saad

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42 Scopus citations

Abstract

The actions of acetylcholine (ACh) on endothelium mainly are mediated through muscarinic receptors, which are members of the G protein-coupled receptor family. In the present study, we show that ACh induces rapid tyrosine phosphorylation and activation of Janus kinase 2 (JAK2) in rat aorta. Upon JAK2 activation, tyrosine phosphorylation of insulin receptor substrate (IRS)-1 is detected. In addition, ACh induces JAK2/IRS-1 and IRS-1/phosphatidylinositol (PI) 3-kinase associations, downstream activation of Akt/protein kinase B, endothelial cell-nitric oxide synthase (eNOS), and extracellular signal-regulated kinase (ERK)-1/2. The pharmacological blockade of JAK2 or PI 3-kinase reduced ACh-stimulated eNOS phosphorylation, NOS activity, and aorta relaxation. These data indicate a new signal transduction pathway for IRS-1/PI 3-kinase/Akt/ eNOS activation and ERK1/2 by means of JAK2 tyrosine phosphorylation stimulated by ACh in vessels. Moreover, we demonstrate that in aorta of obese rats (high-fat diet), there is an impairment in the insulin- and ACh-stimulated IRS-1/PI 3-kinase pathway, leading to reduced activation with lower protein levels of eNOS associated with a hyperactivated ERK/mitogen-activated protein kinase pathway. These results suggest that in aorta of obese rats, there not only is insulin resistance but also ACh resistance, probably mediated by a common signaling pathway that controls the activity and the protein levels of eNOS.

Original languageEnglish (US)
Pages (from-to)1014-1024
Number of pages11
JournalDiabetes
Volume56
Issue number4
DOIs
StatePublished - Apr 1 2007
Externally publishedYes

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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    Zecchin, H. G., Priviero, F. B. M., Souza, C. T., Zecchin, K. G., Prada, P. O., Carvalheira, J. B. C., Velloso, L. A., Antunes, E., & Saad, M. J. A. (2007). Defective insulin and acetylcholine induction of endothelial cell-nitric oxide synthase through insulin receptor substrate/Akt signaling pathway in aorta of obese rats. Diabetes, 56(4), 1014-1024. https://doi.org/10.2337/db05-1147